Fatty acid-peptide-bioconjugated micellar nanocarrier as a new delivery system for l -asparaginase: multi-criteria optim
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ORIGINAL CONTRIBUTION
Fatty acid-peptide-bioconjugated micellar nanocarrier as a new delivery system for L-asparaginase: multi-criteria optimization, characterization, and pharmacokinetic study Hajar Ashrafi 1 & Amir Azadi 1,2 Saeid Daneshamouz 1
&
Soliman Mohammadi-Samani 1,2
&
Younes Ghasemi 2,3
&
Received: 11 August 2020 / Revised: 15 October 2020 / Accepted: 21 October 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract L-Asparaginase-fatty acid bioconjugate was prepared by coupling the carboxyl group of fatty acids to NH2 groups of lysine of the enzyme. In this study, the physicochemical properties of L-asparaginase were modified by incorporating surfactant with this amphiphilic structure. The preparation process of micellar nanocarrier was optimized by a systematic multi-criteria optimization approach in terms of particle size and enzyme activity. The final particle size, PDI, and enzyme activity were 387.6 ± 9.8 nm, 0.341 ± 0.031, and 92.1 ± 1.3%, respectively. Results are in an optimum condition. Furthermore, results showed that the optimized formulation is more resistant to proteolysis, is more stable at different pH (6.5 to 10), and has prolonged plasma half-life (56.8 h) in comparison to the native enzyme. Also, the longevity in the circulation by micellar nanocarriers was confirmed by the data on the pharmacokinetic study. This method can be used as a suitable method to provide a new formulation of L-asparaginase for the treatment of related diseases. Keywords L-Asparaginase . Lipid-protein conjugation . Multi-criteria optimization . Pharmacokinetic
Introduction L-Asparaginase (L-ASNase)
is one of the most efficient drugs in the treatment of lymphoblastic leukemia [1–3]. Today, Escherichia coli strains or Erwinia chrysanthemi are the two primary sources of L-ASNase [4, 5]. Until recently, attempts were made to increase in vitro and in vivo efficacy of LASNase, for instance, its biological half-life, stability, and reduced antigenicity. One successful approach is the chemical modification of L-ASNase, which leads to an increase in enzyme stability by prolonging its biological half-life [6, 7]. Colominic acid is one such compound when conjugated with L-ASNase reduces antigenicity, leading to circulatory half-life * Saeid Daneshamouz [email protected] 1
Department of Pharmaceutics, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
2
Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
3
Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
3–4-fold higher than the native enzyme [8]. Silk fibroin, silk sericine [9, 10], oxidized inulin [11], N,O-carboxymethyl chitosan [12], and carboxymethyl dextran [13] are the other biocompatible compounds. In addition to that, some other nanoparticulate systems are also used for conjugation [14, 15] or immobilization of L-ASNase [16, 17]. Recently, our research group presented a L-ASNase-fatty acid bioconju
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